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Information on EC 1.14.11.2 - procollagen-proline 4-dioxygenase and Organism(s) Rattus norvegicus and UniProt Accession Q6W3E9

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IUBMB Comments
Requires Fe2+ and ascorbate.The enzyme, which is located within the lumen of the endoplasmic reticulum, catalyses the 4-hydroxylation of prolines in -X-Pro-Gly- sequences. The 4-hydroxyproline residues are essential for the formation of the collagen triple helix. The enzyme forms a complex with protein disulfide isomerase and acts not only on procollagen but also on more than 15 other proteins that have collagen-like domains.
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Rattus norvegicus
UNIPROT: Q6W3E9
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Word Map
The taxonomic range for the selected organisms is: Rattus norvegicus
The enzyme appears in selected viruses and cellular organisms
Synonyms
prolyl 4-hydroxylase, prolyl-4-hydroxylase, p4ha1, egln3, p4ha2, hypoxia-inducible factor prolyl hydroxylase, hif prolyl hydroxylase, proline hydroxylase, c-p4h, prolyl-4-hydroxylases, more
SYNONYM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
C-P4H alpha(III)
-
collagen proline hydroxylase
-
-
-
-
egg-laying abnormal-9 prolyl hydroxylase
-
-
EGLN prolyl hydroxylase
-
-
EGLN3 hydroxylase
-
-
HIF prolyl-4-hydroxylase
-
-
hydroxylase, collagen proline
-
-
-
-
hypoxia inducible factor prolyl-4-hydroxylase domain-containing protein
-
-
peptidyl proline hydroxylase
-
-
-
-
procollagen prolyl 4-hydroxylase
-
-
-
-
procollagen-proline dioxygenase
-
-
-
-
proline hydroxylase
-
-
-
-
proline protocollagen hydroxylase
-
-
-
-
proline, 2-oxoglutarate dioxygenase
-
-
-
-
proline,2-oxoglutarate 4-dioxygenase
-
-
-
-
prolyl 4-hydroxylase
prolyl hydroxylase
prolyl-4-hydroxylase alpha I
-
prolyl-4-hydroxylase alpha II
-
-
prolyl-4-hydroxylase alpha1
-
prolyl-glycyl-peptide, 2-oxoglutarate:oxygen oxidoreductase, 4-hydroxylating
-
-
-
-
prolylprotocollagen dioxygenase
-
-
-
-
prolylprotocollagen hydroxylase
-
-
-
-
protocollagen hydroxylase
-
-
-
-
protocollagen proline 4-hydroxylase
-
-
-
-
protocollagen proline dioxygenase
-
-
-
-
protocollagen proline hydroxylase
-
-
-
-
protocollagen prolyl hydroxylase
-
-
-
-
type I proly 4-hydroxylase
-
-
additional information
-
the enzyme belongs to the P4H enzyme family of the 2-oxoglutarate-dependent dioxygenases
REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
procollagen L-proline + 2-oxoglutarate + O2 = procollagen trans-4-hydroxy-L-proline + succinate + CO2
show the reaction diagram
reaction mechanism involving ascorbate, which not required for the hydroxylation reaction part, but for the uncoupled cedarboxylation, overview
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
decarboxylation
-
-
-
-
redox reaction
-
-
-
-
oxidation
-
-
-
-
reduction
-
-
-
-
hydroxylation
-
-
-
-
PATHWAY SOURCE
PATHWAYS
-
-
SYSTEMATIC NAME
IUBMB Comments
procollagen-L-proline,2-oxoglutarate:oxygen oxidoreductase (4-hydroxylating)
Requires Fe2+ and ascorbate.The enzyme, which is located within the lumen of the endoplasmic reticulum, catalyses the 4-hydroxylation of prolines in -X-Pro-Gly- sequences. The 4-hydroxyproline residues are essential for the formation of the collagen triple helix. The enzyme forms a complex with protein disulfide isomerase and acts not only on procollagen but also on more than 15 other proteins that have collagen-like domains.
CAS REGISTRY NUMBER
COMMENTARY hide
9028-06-2
-
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
procollagen L-proline + 2-oxoglutarate + O2
procollagen trans-4-hydroxy-L-proline + succinate + CO2
show the reaction diagram
-
-
-
?
(Gly-Ala-Pro)n + 2-oxoglutarate + O2
4-hydroxyproline containing peptide + succinate + CO2
show the reaction diagram
-
active substrate
-
?
(Gly-Pro-Ala)n + 2-oxoglutarate + O2
4-hydroxyproline containing peptide + succinate + CO2
show the reaction diagram
-
poor substrate
-
?
(L-Pro-L-Pro-Gly)10 + 2-oxoglutarate + O2
(L-Pro-L-Pro-Gly)10-trans-4-hydroxy-L-proline + succinate + CO2
show the reaction diagram
-
-
-
-
r
(L-Pro-L-Pro-Gly)5 + 2-oxoglutarate + O2
(L-Pro-L-Pro-Gly)5-trans-4-hydroxy-L-proline + succinate + CO2
show the reaction diagram
-
-
-
-
r
(Pro-Gly-Pro)n + 2-oxoglutarate + O2
4-hydroxyproline containing peptide + succinate + CO2
show the reaction diagram
-
active substrate
-
?
(Pro-Pro-Gly)n + 2-oxoglutarate + O2
(Pro-4-hydroxy-Pro-Gly)n + succinate + CO2
show the reaction diagram
-
n: 1,5,10
n: 1,5,10
?
hypoxia-inducible factor L-proline + 2-oxoglutarate + O2
hypoxia inducible factor trans-4-hydroxy-L-proline + succinate + CO2
show the reaction diagram
-
-
-
-
?
hypoxia-inducible transcription factor + 2-oxoglutarate + O2
hypoxia-inducible transcription factor trans-4-hydroxy-L-proline + succinate + CO2
show the reaction diagram
procollagen L-proline + 2-oxoglutarate + O2
procollagen trans-4-hydroxy-L-proline + succinate + CO2
show the reaction diagram
proline containing peptide + 2-oxoglutarate + O2
4-hydroxyproline containing peptide + succinate + CO2
show the reaction diagram
protocollagen + 2-oxoglutarate + O2
4-hydroxyproline containing protocollagen + succinate + CO2
show the reaction diagram
-
-
-
?
additional information
?
-
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
procollagen L-proline + 2-oxoglutarate + O2
procollagen trans-4-hydroxy-L-proline + succinate + CO2
show the reaction diagram
-
-
-
?
hypoxia-inducible transcription factor + 2-oxoglutarate + O2
hypoxia-inducible transcription factor trans-4-hydroxy-L-proline + succinate + CO2
show the reaction diagram
-
i.e. HIF, an alphabetaheterodimer, in which the stability of the alpha-subunti is regulated in an oxygen-dependent manner. Hydroxylation of one or two critical proline residues in the oxygen-dependent degradation domain leads to proteasomal degradation of the protein under normic conditions, while under hypoxic conditions the oxygen-requiring hydroxylation is inhibited and HIF-alpha escapes degradation and dimerizes with HIF-beta, overview
-
-
?
procollagen L-proline + 2-oxoglutarate + O2
procollagen trans-4-hydroxy-L-proline + succinate + CO2
show the reaction diagram
COFACTOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
2-oxoglutarate
ascorbate
D-isoascorbate
-
can replace ascorbate
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
additional information
-
EGLN3 contains a conserved iron-binding motif, of which two histidine residues, His135 and His196, are critical for its enzymatic activity
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
1,10-phenanthroline
1,4-dihydrophenanthroline-4-one-3-carboxylic acid
-
potent competitive inhibitor of collagen hydroxylation in the oestradiol-stimulated uterus in vivo
2,2'-dipyridyl
8-(N-butyl-N-ethylcarbamoyl)-1,4-dihydrophenanthrolin-4-one-3-carboxylic acid
-
potent competitive inhibitor of collagen hydroxylation in the oestradiol-stimulated uterus in vivo
8-hydroxyquinoline
-
inhibits at a concentration higher than the Fe2+ concentration in the reaction mixture
alpha,alpha'-dipyridyl
-
an Fe2+ chelator
antimycin A
-
18% inhibition at 0.02 mM
Cd2+
-
competitive versus Fe2+
ciclopirox olamine
-
an Fe2+ chelator
Co2+
-
competitive versus Fe2+
Cupferron
-
28% inhibition at 0.02 mM
desferrioxamine
diethyldithiocarbamate
-
10% inhibition at 0.02 mM
Diethylenetriaminepentaacetic acid
-
inhibits at a concentration higher than the Fe2+ concentration in the reaction mixture
dimethyl oxalylglycine
-
DMOG, the effect is HIF-independent
dithiothreitol
-
powerful inhibitor at 1 mM
gelatin
-
commercial, inhibitor
-
HOE077
-
decrease in enzyme activity by 15%
Ketomalonate
-
100% inhibition at 1 mM, acts by chelating ferrous ion rather than by competing with alpha-ketoglutarate
L-mimosine
-
50 mg/kg/day for 2 weeks
malonate
-
19% inhibition at 1 mM
N-Hydroxyethylenediaminetriacetic acid
-
inhibits at a concentration higher than the Fe2+ concentration in the reaction mixture
Ni2+
-
competitive versus Fe2+
oxalate
-
34% inhibition at 1 mM
phenanthrolines
-
-
-
propyl gallate
-
100% inhibition at 2 mM
rosiglitazone
-
decrease in enzyme activity by 32.3%
succinate
-
51% inhibition at 1 mM
trifluorothienylbutanedione
-
48% inhibition at 0.05 mM
Zn2+
-
competitive versus Fe2+
additional information
-
hypoxia inhibits the enzyme
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
1,10-phenanthroline
-
stimulates if it reaches an equimolar concentration with Fe2+
8-hydroxyquinoline
-
stimulates if it reaches an equimolar concentration with Fe2+
alpha,alpha'-dipyridyl
-
stimulates if it reaches an equimolar concentration with Fe2+
ascorbate
-
required for the decarboxylation reaction step
bovine serum albumin
-
activation
-
catalase
-
activation
-
Diethylenetriaminepentaacetic acid
-
5fold stimulation at 0.2 mM, equimolar with Fe2+
dithiothreitol
-
activation
EDTA
-
1.4fold stimulation at 0.2 mM, equimolar with Fe2+
glycoletherdiamine tetraacetic acid
-
1.4fold stimulation at 0.2 mM, equimolar with Fe2+, and 2.8fold stimulation at 1 mM
N-Hydroxyethylenediaminetriacetic acid
-
5fold stimulation at 0.2 mM, equimolar with Fe2+
nitrilotriacetic acid
-
6fold stimulation at 0.2 mM, equimolar with Fe2+, and 7.6fold stimulation at 1 mM
nucleoside triphosphates
-
stimulate
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.01 - 0.03
(L-Pro-L-Pro-Gly)10
-
-
-
0.1 - 0.5
(L-Pro-L-Pro-Gly)5
-
-
-
0.00000001
Protocollagen
-
-
-
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
1.295
-
purified enzyme
1.3
-
purified enzyme
additional information
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
-
SwissProt
Manually annotated by BRENDA team
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
rat abdominal aortas
Manually annotated by BRENDA team
-
a cell line with myogenic potential derived from embryonic rat heart
Manually annotated by BRENDA team
-
treatment with ascorbate in a hypoxic condition for 24 h results in the maximal increase of hydroxyproline by 1.8-fold. The presence of cobalt chloride can substitute for hypoxic condition
Manually annotated by BRENDA team
-
highest enzyme activity
Manually annotated by BRENDA team
-
ATCC ROS 17/2.8, strong expression of type I alpha subunit
Manually annotated by BRENDA team
additional information
-
the enzyme activity decreases with age in all the tissues studied
Manually annotated by BRENDA team
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
metabolism
-
pharmacologic inactivation of EGLN3 hydroxylase results in activation of the canonical NF-kappaB pathway
physiological function
additional information
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION?
P4HA3_RAT
544
0
61165
Swiss-Prot
Secretory Pathway (Reliability: 1)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
230000 - 240000
-
gel filtration
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
tetramer
additional information
-
the beta-subunit is identical to the beta-subunit of the chaperone protein disulfide isomerase, EC 5.3.4.1. The beta-subunit is responsible for keeping the catalytic alpha-subunit active, in non-aggregated conformation and for retaining the enzyme within the lumen of the endoplasmic reticulum via its C-terminal retention signal
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
H196R
-
inactive mutant
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
labile in tissue extracts
-
stabilization by NaCl, detergents
-
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
of the beta-subunit using ammonium sulfate fractionation, chromatography on preimmune IgG column and immunoadsorbent column, and gel filtration
-
separation of 4-hydroxylase activity from 3-hydroxylase activity using affinity chromatography and gel filtration
-
using affinity chromatography on a column containing a polypeptide substrate of the enzyme linked to agarose, elution of the enzyme with a second peptide substrate and separation of the enzyme from this peptide by gel filtration
-
using affinity chromatography on a column containing poly-(L-proline) linked to agarose, elution with the same polypeptide of a lower molecular weight, and gel filtration
-
using ammonium sulfate fractionation and affinity chromatography
-
using ammonium sulfate precipitation, affinity chromatography on poly(L-proline) column and gel filtration
-
using fractionating precipitations, ion-exchange chromatographies and gel filtrations
-
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
gene P4halpha1, quantitative real-time PCR enzyme expression analysis
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
after apoptosis of H9c2 cells is induced by DOX, PHD3 expression is upregulated in a time-dependent manner, whereas the expression of PHD1 or PHD2 is constant
-
the enzyme is induced by mechanical stretch on the vessel wall, an important stimulus that also induces collagen remodeling
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
analysis
-
assay method for screening the inhibitors of prolyl 4-hydroxylase to treat fibrosis. The assay uses rat hepatic stellate HSC-6 cells and cobalt chloride as a substitue for a hypoxic condition, the procedure takes three days after treatment with agents
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Kivirikko, K.I.; Myllyl, R.
The hydroxylation of prolyl and lysyl residues
Enzymol. Post- transl. Modif. Proteins (Freedman, R. B. , Hawkins, H. C. , eds. ) Academic Press, New York
1
53-104
1980
Gallus gallus, Homo sapiens, Rattus norvegicus
-
Manually annotated by BRENDA team
Kivirikko, K.I.; Myllyl, R.
Posttranslational enzymes in the biosynthesis of collagen: intracellular enzymes
Methods Enzymol.
82
245-304
1982
Gallus gallus, Homo sapiens, Rattus norvegicus
Manually annotated by BRENDA team
Takeda, K.; Katoh, F.; Kawai, S.; Konno, K.
Stimulation of prolyl hydroxylase activity by chelating agents
Arch. Biochem. Biophys.
197
273-276
1979
Rattus norvegicus
Manually annotated by BRENDA team
Tryggvason, K.; Majamaa, K.; Kivirikko, K.I.
Prolyl 3-hydroxylase and 4-hydroxylase activities in certain rat and chick-embryo tissues and age-related changes in their activities in the rat
Biochem. J.
178
127-131
1979
Gallus gallus, Rattus norvegicus, Rattus norvegicus Sprague-Dawley
Manually annotated by BRENDA team
Tryggvason, K.; Risteli, J.; Kivirikko, K.I.
Separation of prolyl 3-hydroxylase and 4-hydroxylase activities and the 4-hydroxyproline requirement for synthesis of 3-hydroxyproline
Biochem. Biophys. Res. Commun.
76
275-281
1977
Rattus norvegicus, Rattus norvegicus Sprague-Dawley
Manually annotated by BRENDA team
Risteli, J.; Tuderman, L.; Kivirikko, K.I.
Intracellular enzymes of collagen biosynthesis in rat liver as a function of age and in hepatic injury induced by dimethylnitrosamine. Purification of rat prolyl hydroxylase and comparison of changes in prolyl hydroxylase activity with changes in immunoreactive prolyl hydroxylase
Biochem. J.
158
369-376
1976
Rattus norvegicus
Manually annotated by BRENDA team
Adams, E.; Lamon, M.
Prolyl hydroxylase of earthworms. Substrate specificity of an enzyme from the subcuticular epithelium
J. Biol. Chem.
252
7591-7597
1977
Lumbricus terrestris, Rattus norvegicus
Manually annotated by BRENDA team
Hutton, J.J.; Tappel, A.L.; Udenfried, S.
Cofactor and substrate requirements of collagen proline hydroxylase
Arch. Biochem. Biophys.
118
231-240
1967
Cavia porcellus, Gallus gallus, Rattus norvegicus
-
Manually annotated by BRENDA team
Franklin, T.J.; Morris, W.P.; Edwards, P.N.; Large, M.S.; Stephenson, R.
Inhibition of prolyl 4-hydroxylase in vitro and in vivo by members of a novel series of phenanthrolinones
Biochem. J.
353
333-338
2001
Gallus gallus, Homo sapiens, Rattus norvegicus, Rattus norvegicus Sprague-Dawley
Manually annotated by BRENDA team
Nissi, R.; Bohling, T.; Autio-Harmainen, H.
Immunofluorescence localization of prolyl 4-hydroxylase isoenzymes and type I and II collagens in bone tumours: type I enzyme predominates in osteosarcomas and chondrosarcomas, whereas type II enzyme predominates in their benign counterparts
Acta Histochem.
106
111-121
2004
Homo sapiens, Rattus norvegicus
Manually annotated by BRENDA team
Hofbauer, K.h.; Gess, B.; Lohaus, C.; Meyer, H.E.; Katschinski, D.; Kurtz, A.
Oxygen tension regulates the expression of a group of procollagen hydroxylases
Eur. J. Biochem.
270
4515-4522
2003
Rattus norvegicus, Rattus norvegicus (P54001)
Manually annotated by BRENDA team
Kukkola, L.; Hieta, R.; Kivirikko, K.I.; Myllyharju, J.
Identification and characterization of a third human, rat, and mouse collagen prolyl 4-hydroxylase isoenzyme
J. Biol. Chem.
278
47685-47693
2003
Rattus norvegicus (Q6W3E9), Mus musculus (Q6W3F0), Mus musculus, Homo sapiens (Q7Z4N8), Homo sapiens
Manually annotated by BRENDA team
Li, N.; Yi, F.; Sundy, C.M.; Chen, L.; Hilliker, M.L.; Donley, D.K.; Muldoon, D.B.; Li, P.L.
Expression and actions of HIF prolyl-4-hydroxylase in the rat kidneys
Am. J. Physiol. Renal Physiol.
292
F207-F216
2007
Rattus norvegicus
Manually annotated by BRENDA team
Choi, H.J.; Soh, Y.
An assay method for screening inhibitors of prolyl 4-hydroxylase in immortalized rat hepatic stellate HSC-T6 cells
J. Appl. Pharmacol.
15
261-265
2007
Rattus norvegicus
-
Manually annotated by BRENDA team
Myllyharju, J.
Prolyl 4-hydroxylases, key enzymes in the synthesis of collagens and regulation of the response to hypoxia, and their roles as treatment targets
Ann. Med.
40
402-417
2008
Caenorhabditis elegans, Chlamydomonas reinhardtii, Drosophila melanogaster, Homo sapiens, Mus musculus, Rattus norvegicus
Manually annotated by BRENDA team
Liu, Y.; Huo, Z.; Yan, B.; Lin, X.; Zhou, Z.N.; Liang, X.; Zhu, W.; Liang, D.; Li, L.; Liu, Y.; Zhao, H.; Sun, Y.; Chen, Y.H.
Prolyl hydroxylase 3 interacts with Bcl-2 to regulate doxorubicin-induced apoptosis in H9c2 cells
Biochem. Biophys. Res. Commun.
401
231-237
2010
Rattus norvegicus
Manually annotated by BRENDA team
Fu, J.; Taubman, M.B.
Prolyl hydroxylase EGLN3 regulates skeletal myoblast differentiation through an NF-kappaB-dependent pathway
J. Biol. Chem.
285
8927-8935
2010
Rattus norvegicus
Manually annotated by BRENDA team
Liu, X.; Huang, X.; Chen, L.; Zhang, Y.; Li, M.; Wang, L.; Ge, C.; Wang, H.; Zhang, M.
Mechanical stretch promotes matrix metalloproteinase-2 and prolyl-4-hydroxylase alpha1 production in human aortic smooth muscle cells via Akt-p38 MAPK-JNK signaling
Int. J. Biochem. Cell Biol.
62
15-23
2015
Homo sapiens (P13674), Homo sapiens, Rattus norvegicus (P54001), Rattus norvegicus Wistar (P54001)
Manually annotated by BRENDA team